Aquaporins are widely but differentially expressed in plant and animal tissues. These transmembrane channels facilitate passive transport of water and specific solutes, like urea and glycerol, thereby crucially affecting fluid balance in mammalian and other organisms. Members of these channels have been shown to contribute to the pathology of various diseases and disorders, including metabolic disease, inflammatory disease, bone disease, atherosclerosis, allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis. Mammalian aquaporins can be divided into at least three subfamilies: the aquaporin subfamily that conducts water, the aquaglyceroporins, which allow the passage of water and small uncharged molecules like glycerol and urea, and a third group of unorthodox aquaporins which remain poorly characterized at present.
Aquaporin 3, 7 and 9 belong to the aquaglyceroporins and are structurally related, but expressed in different cells and tissues and thus have been ascribed specific functions. Aquaporin 9 (AQP9) is a glycerol channel that is expressed in liver, lung, and skin tissues, gastrointestinal tissues, tissues of the male and female reproductive tract, and hematopoietic cells (The Human Protein Atlas, www.proteinatlas.org). Thus, AQP9 channels might represent good targets for drug development since agents modulating these channels would be useful in the treatment of disorders and diseases, where its function or dysfunction contributes to the development or maintenance of disease. Indeed, AQP9 has been implicated in pathophysiological processes in a variety of diseases, such as diabetes, atherosclerosis, disuse osteoporosis, non-alcoholic fatty liver disease, acute kidney injury, kidney ischemia-reperfusion injury, inflammatory diseases including but not limited to inflammatory bowel disease, psoriasis, allergic contact dermatitis, and rheumatoid arthritis.
Approximately 90% of all plasma glycerol is converted to glucose by the liver. In states of dysregulated glucose metabolism, such as type 2 diabetes (characterized by elevated blood glucose levels and insulin resistance), gluconeogenesis from glycerol accounts for 10% of hepatic glucose production in patients (Puhakainen, I. et. al., J. Clin. Endocrinol. Metab., 1992, 75, 789-794). This amounts to a daily production of 500 mmol (about 90 gram) of glucose in average obese type 2 patients, compared to 150 mmol in healthy individuals of normal weight.
Studies of AQP9 knockout mice have clearly demonstrated the pathophysiological relevance of glycerol channels in liver through effects on glycerol metabolism. Specifically, AQP9 is essential for efficient glycerol uptake into hepatocytes and is crucial for hepatic glucose production. (Jelen et al, J. Biol. Chem., 2011, 286, 44319-44325). In AQP9-deficient diabetic mice, blood glucose levels were normal 2 hours after a meal, while blood glucose was ˜30% elevated in equally treated aquaporin 9 wildtype diabetic mice (Rojek, A. M., et al., Proc. Natl. Acad. Sci. USA, 2007, 104, 3609-3614). These results suggest that inhibition of AQP9 could reduce plasma glucose levels after a meal and that AQP9 is a potential drug target in diabetic treatment.
It would be desirable to provide compounds having high affinity for aquaporin 9 and the ability to modulate aquaporin 9 or to diminish deregulated hepatocyte glucose output in metabolic disease as characterized by hyperglycemia.